I recently came across an article about biosimilar insulins and was quite surprised to learn about the potential problems we and our patients may face with future insulin products.

Although I do not know of any biosimilar insulins yet in the United States, this issue is very important “because impure proteins {in biosimilar insulins} may be recognized by the body as foreign and stimulate the generation of antibodies. These occasionally can cause allergic reactions, and the allergy can become generalized to attack the body’s own insulin. Furthermore, production of lots of antibodies can neutralize the effectiveness of insulin itself, which then loses efficacy.” We saw that happen with beef insulin and beef/pork insulins in the past.

Here are some alarming facts from the article by Philip Home in Sept 2011 issue of Diabetes Voice:

In 1980, the major technical advance occurred when” bacteria and yeast were bioengineered with the genes that included the template for human insulin. The cell culture process then multiplies the bacteria/yeast while the genes are turned on to produce the insulin precursor….From these, theinsulin must be extracted and purified to remove all the bacterial/yeast proteins and other biochemical molecules, before being processed to derive the insulin from the precursor protein.”

“As modern insulins come off patent, many companies are expected to try to enter the market with copies of current branded insulin called biosimilar insulins.”

It is important to note that “chemical medications like metformin and simvastatin, have a defined chemical structure” It is not difficult to show regulators that the chemical they produce is the same as the original” (Of course, as we know, the delivery of the medication may not be the same as the branded original version of any medications)

“Proteins like insulin are different. They are built from a small number of identical small molecules (amino acids), the same ones often being used many times over, but in a critically important order. The molecule then folds in complex ways which are necessary to its biological action. Showing that a protein molecule like insulin has the right number of amino acid components is easy, but showing that they are all in the right order, and that the molecule is folded correctly, is very difficult.”

“If a small amount of a manufactured protein is not perfect, then it may cause the production of antibodies with repeated injectionin patients, and demonstrating that such impurities do not exist in very small proportions is well-nigh impossible.”

Those are the reasons that “drug regulators do not refer to ‘generic insulin’ (as they do for generic medications like metformin) but have introduced the term ‘biosimilar insulin’.”

Currently during 2011-2013 “several important insulin analogues used in diabetes care are coming off patent, including insulins aspart, glargine, and lispro. Manufacturers in America, China, India, Israel and the UK are known to be interested in producing and marketing biosimilar insulins, insulin glargine being the principle target.”

“Meanwhile, the development of new insulins continues, so new premium priced products are already in advanced development from some insulin manufacturers”

An important issue will be “whether a pharmacist faced with a physician’s prescription can, or can be required to, substitute a cheaper version of the same insulin for the branded insulin a person with diabetes has been using.”

Modern insulin analogs like Glargine (Lantus) are controlled and approved by the FDA. When a patent expires, others can produce the previously protected product (like Glargine), but that does not mean that they can sell the product. The FDA must approve the specific supply. The company must apply to the FDA for approval. I believe the term "biosimilar" refers to products that are similar enough biologically that they can perform functionally as an equivalent to another product. In this day and age of very complex products, products can vary by little bits here and there and while different, they may be able to used as replacements. Sometimes the only differences between the products is the purity and additives.

In this specific case, an Indian company Biocon has developed what seem to be bioidentical insulins, like Glargine for sale in other countries like India. When the patent on Lantus expires, Biocon will be posititioned to sell their product "Basalog" which is "biosimilar" to Lantus in the US. But there may well be differences in purity and additives which mean that the FDA delays or declines approval. Should Biocon fail to get approval for Basalog as a generic replacement for Lantus, it could still seek approval to sell Basalog as a different insulin formuation.

Joan, the "biosimilar insulins" are insulins in this new class may resemble in structure the insulins that have lost their patents, but the impurities that may be found in them can potentially cause the immune response mentioned in the initial presentation in this blog. The purified insulins we have that still have their patents have been produced by a very complex process that purifies them of impurities. It is possible that the process used to create biosimilar insulins may not remove all the impurities. I always teach nurses what lipoatrophy looks like. We saw this with beef insulin and sometimes beef-pork insulins. I hope it does not happen with some of the bioswimilar insulins, but it is a good idea to be aware of what lipoatrophy looks like.(see picture below)

Pfizer is entering the injected insulin market with Biocon. "Pfizer and Biocon, a biopharmaceutical company in India, recently announced a multimillion dollar partnership that will have Pfizer marketing biosimilar insulins, which in the US are designated as so-called 'follow-on drugs' by the FDA (aka a new brand in an existing therapeutic class)."

"In essence, it is generic insulin, but is distinctly different because of the unique nature of insulin. Unlike something like aspirin, which is a formula of chemicals that can be made by anyone in the same way, insulin can be so highly influenced in production that Regulators will only it to be labeled “similar” — not identical. Hence, biosimilar insulins."

Thanks to you both Pat and Brian. I have been in diabetes long enough to remember the hypertrophy from the Beef +/or Beef/Pork. The launch of these newer insulins will likely bring a challenge to all educators. It's so great to have this forum to assist eachother in providing top notch care to our patients!

I think we also have to realize that the most likely outcome of this adventure is that Pfizer (which has bombed in the insulin market with Exubera) is poised to renter the insulin market in collaboration with Biocon. Pfizer has essentially bought into four of the insulin products from Biocon. While we might have some concern about the purity and quality of these insulins, the Biocon products are approved in 27 countries and Pfizer certainly has the capability and expertise to bring these products up to standard for US approval. I am somewhat cautious about complaints about quality before the fact as perhaps being early spin.

ps. I also like to "investigate" authors. Philip Home, while respected, former chair of the IDF, declares that he has recieved grants from : Novo Nordisk; sanofi-aventis; Bristol-Myers Squibb Company; GlaxoSmithKline, ..... but not Pfizer. I'm not saying he has twisted anything, but he does have a financial conflict of interest in the matter.

Thanks, again, Brian, You always have a wealth of in depth information. I agree that the partnership with PFIZER is comforting somewhat because they are a reputable drug company and have the resources to do it right